Chemically induced long-term potentiation (cLTP) could potentially work by directly stimulating the biochemical machinery that underlies synaptic plasticity, bypassing the need for synaptic activation. Previous reports suggested that agents that raise cAMP concentration might have this capability. We examined the cLTP induced in acute slices by application of Sp-cAMPS or a combination of the adenylyl cyclase activator, forskolin, and the phosphodiesterase inhibitor, rolipram. Under our conditions, cLTP was induced but only if inhibition was reduced. We found that this form of cLTP was blocked by a N-methyl-D-aspartate receptor (NMDAR) antagonist and required the low-frequency test stimulation typically used to monitor the strength of synapses. Interestingly, similar LTP could be induced by lowering the Mg2+ concentration of the ACSF during forskolin/rolipram or Sp-cAMPS application or even by just lowering Mg2+ concentration alone. This LTP was also NMDAR dependent and required only a few (∼5) low-frequency stimuli for its induction. The finding that even low-frequency synaptic stimulation was sufficient for LTP induction indicates that a highly sensitized plasticity state was generated. The fact that some stimulation was required means that potentiation is probably restricted to the stimulated axons, limiting the usefulness of this form of cLTP. However, when similar experiments were conducted using slice cultures, potentiation occurred without test stimuli, probably because the CA3–CA1 connections are extensive and because presynaptic spontaneous activity is sufficient to fulfill the activity requirement. As in acute slices, the potentiation was blocked by an NMDAR antagonist. Our general conclusion is that the induction of LTP caused by elevating cAMP requires presynaptic activity and NMDA channel opening. The method of inducing cLTP in slice cultures will be useful when it is desirable to produce NMDAR-dependent LTP in a large fraction of synapses.

--- Update 3/14/2013 ---

Hello and welcome to the thread that spawned the CILTEP stack. That stands for "Chemically Induced Long TErm Potentiation". This summary is a work in progress.

Here's my current stack:

PDE 4 and others inhibition:

2x450 mg Now Artichoke Extract. Other artichoke extract brands have been reported to work too.

cAMP Increase:

4mg of Forskolin from uncapping and weighing out the correct proportion of Better Body Sports 95% pure C-Bolic capsules. Other forskolin supplements have been reported to work too. To get the right amount of Forskolin from a C-Bolic capsule containing 25mg of forskolin you want to multiply the weight of the emptied out material by 4/25 to get 4mg of forskolin assuming it's evenly mixed.

Dopamine Metabolism Support (Important for avoiding fatigue due to increased dopamine metabolism!):

500mg Phenylalanine (Lower doses work better for some)

B-Vitamin Complex

200mg Caffeine (Optional)

For mitigating forskolin's effects on Acetylcholinesterase:

800mg ALCAR (Generally 200mg of ALCAR for every 1mg of forskolin)

An earlier recommendation before we started adding ALCAR to counteract forskolin's effects was to take the following in the afternoon:

350mg Jarrow N-Acetyl L-Tyrosine (Possibly no longer necessary)

I don't take this now that I've added ALCAR to the stack.

I have been taking the artichoke extract variant of this stack almost every day since late 2011 with only positive effects. There have been several attempts to replace Artichoke extract with other PDE4 inhibitors (Quercetin and/or Hesperidin) by myself and other forum users but they have not been tolerable for most people who have tried them.

These are some of the effects myself and others have reported:

Improved mood and motivation

Increased ability to study and retain information

Improved long-term memory

Some people have reported nothing from taking the stack. Some users have reported tiredness after taking the stack for a while. With the later addition of dopamine metabolism supporting supplements and a forskolin dose of less than 5mg this has been less of an issue. Some users have reported diminished working memory while taking the stack, especially when taking higher does of forskolin or when taking the stack with Quercetin, which is not recommended.

Standard Disclaimer: This is a research thread. The evidence for this stack is largely theoretical and anecdotal. Proceed at your own risk, preferably after reading the whole thread. Please check with your doctor before starting a new supplement regime, especially if you have any health conditions.

Please feel free to add your comments and questions to the thread. The stack is still in active development, as you will see if you visit the later portions of the thread. The thread is a great read and contains lots of interesting scientific and anecdotal information so enjoy it. Thanks!

--- Update 4/09/2013 ---

I have been experimenting with Zembrin as a replacement for Artichoke extract. Zembrin is an extract of the plant Sceletium Tortuosum (a.k.a Kanna). Sceletium Tortuosum grows natively in South Africa and has been used in traditional medicine there for centuries. One of its components, mesembrenone, is a potent and relatively selective PDE4 inhibitor. I have only been using this stack for about a week, but so far results are good. My initial post on the thread about Zembrin is here. I have also made several follow-up posts about my experience. Artichoke Extract is a lot cheaper than Zembrin so it may be a better option for people on a budget. Myself and other users have reported good results with various other Kanna preparations which are also cheaper than Zembrin, so that may be another option. Please note that Zembrin and Kanna affect serotonin via an SSRI like effect and thus should probably not be taken by people who are currently taking SSRIs or other serotonin affecting drugs.

with me is Roy Krebs of http://www.naturalstacks.com . Besides talking about the history and the mechanism of action of the stack and how awesome Longecity is we announced that we're going to be coming out this month with the first ever CILTEP all-in-one supplement!!

With regards to cycling, I take the stack every day. Some people take the weekends off or only take CILTEP when they need it. When taking days off I usually supplement with N-Acetyl-L-Tyrosine or L-Phenylalanine to avoid feeling less energetic than I would like.

If you read the thread, there are a few reports of the stack reversing tolerance to stimulants and/or increasing their effects. I would avoid taking CILTEP and stimulants like nicotine together. I haven't had any issues with reasonable amounts of caffeine though.

-- Update 03/12/2014--

There has been some discussion of various possible additions to the stack along with some experiments with D1/D2 affecting herbals. Results have been mixed.

Some have suggested that proper zinc and magnesium intake is required for optimal stack performance.

Yeah, its been talked about before quite a bit, all nootropics do influence electropsyilogy and hence LTP and LTD. AMPAkine obviously increase LTP etc, its hard to translate form network effects to global cognitive function. Learnings is inhibited by prior learning(LTP)

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Aniracetam is a positive allosteric modulator of the AMPA receptor, so I'd start there. It obviously is not as strong as the other ampakines (CX-516, CX-717, etc.), but according to the research I've seen it does have some effect. I believe the other 'racetams, does have an effect on this as well.

Ultimately, what we would want is something that not only improves long-term memory -- but rather -- enhances our ability to learn instantly. A while ago, I read about the italian researchers who had found that over-expressing a certain protein allowed for >200% of visual memory ability. Ideally, what we would want to is enhance visual memory ability (you see, you remember), but selectively, and lower latent inhibition while still strengthening executive functioning through DLPFC and other structures in the frontal cortex.

Reading Tesla's autobiography, I realize that many of those geniuses actually have an over-developed imagination; meaning, they rely highly on visual images that their mind creates. So for instance, when Tesla got an idea about some machine, he would imagine it in his mind, and then tweak it for several hours, look over it again, and then finally, do the actual design. Einstein also said: "Imagination is more important than knowledge", and I realize that he is true.

my question regarding the original study posted is rolipram a pde4 inhibitor neccesary or can forskoliin by itself be used?

interestingly i was just reading about how the 5ht2a receptor (also known for synethesia) uninhibits phototgraphic memory and automatic processing of say equations, if that receptor can be disinhibited we can activate savant like latent abilities.

im also trying to get more research done on glutamatergics, im exhausted at the moment but ill get back to it when i have time for it.

An indepth study of electropsyology is vital for understanding the CNS. Learning about LTP is definitly recommended. It can allow you a method to assess the effect of an alteration on the whole.....

"interestingly i was just reading about how the 5ht2a receptor (also known for synethesia) uninhibits phototgraphic memory and automatic processing of say equations"

Yes I would agree with this from a neuropharamcological point of view. Interestingly this is through a modification of electrophysiology and hence is expressed in a modification of the glutamate system. The glutamate system is actually very complex, such things as synaptic location of receptors and subunit composition (etc) are responisble for varying forms of plasticity and hence serve cognition in different ways. Because of the Drug like nature of 5-htp2A agonist im not going to discuss the how, what and why.

I understand that low latent inhibtion results in a brain that is substanially different from more typical brains. I imagine that there is far greater parallel processing resulting in a system that is more sculpted from the subconcious workings than concious. The brain is more defined by the environment and needs rather than a Self,This may have advantages given the increased processing of the subcon mind. I think most winners are in this state, their concious mind is a supervisor maybe rather than a participant . Interestingly low latent inhibition is typical in autism and some forms of ADHD. These deficits are primarily a function of low executive function in varying capacities, While schiz which maybe an extension of autism/adhd and could be caused by such lack of 'executive function' that the extended fails to support adaquate signal transduction to ensure biological viability.

very well said as well, Consciousness, cognitive function, the mechanisms and systems to it wont be easy to understand at all, it's going to take immense expertise. have to hit the books, etc, studies and in the field, and stay up to date and ahead of the curve, to understand it all better. regarding the 5htp mention, i don't really understand the nature of it all very well but i would speculate allosteric modulators rather then direct agonist would be the choice to choose. Consciousness and cognitive function are very much intertwined. Were going to have to unlock the secrets of the brain, in order to unlock higher cognitive capabilities. It is sort of a chicken and the egg scenario.

I've been taking some supplement combos related to the mechanism of action described in this thread recently and have had some interesting results. There are some pretty big caveats to playing around with these pathways, mainly the potential for DOPAC buildup. (http://www.ncbi.nlm..../pubmed/9334890) which can be mediated to some extent by MAOI-B inhibitors (http://www.ncbi.nlm....pubmed/16891770), and potential side effects of inhibiting PDE 1 through 5.

SourcePicower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

AbstractMemory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.

I think that there must be more to ltp then just camp signal pathway there must be more going on then just camp. Check out this video its related to LTP and about sleeping, memory consolidation. Finding a way to enhance sleep- rem sleep, will enhance learning.http://fora.tv/2009/..._Sleeping_Brain

I think that there must be more to ltp then just camp signal pathway there must be more going on then just camp. Check out this video its related to LTP and about sleeping, memory consolidation. Finding a way to enhance sleep- rem sleep, will enhance learning.http://fora.tv/2009/..._Sleeping_Brain

I'm not saying CREB/cAMP is the ONLY way to increase memory, it just seems that, based on the above cited studies, that this is a pathway that must be present or LTP is not possible.

What I'm trying to do here is to stimulate discussion about a recently discovered drug modifiable neurochemical mechanism of action related to learning and memory and thus a potential unexplored category of nootropics. I'm not trying to disprove the need for a good night's sleep.

Mindfulness targeted training have been shown to improve executive functioning control. Despite that, I only think modafinil have been shown to improve executive functioning (namely, working memory) in healthy young individuals. That said, if you do have any symptoms of ADHD, amphetamine(s) are your immediate best bet for executive function improvement.

Cyclic-AMP and CREB are now targets for drugs. In 1998 Kandel's team injected aging mice with a failed antidepressant called Rolipram, which prevents the breakdown of cyclic-AMP by blocking an enzyme called phosphodiesterase-4. The hope was the drug would boost old, tiring brain cells. Rolipram, though developed in the late 1980s, never made it because it did not work well and caused nausea and vomiting. But, sure enough, old mice on Rolipram began navigating mazes faster.Kandel shared the amazing results with his friend, Walter Gilbert, a Nobel laureate at Harvard who founded Biogen. Gilbert contacted venture capitalist Jonathan Fleming of Oxford Bioscience Partners, who helped raise $38 million to form Memory Pharmaceuticals. Axel Unterbeck, then head of dementia research at Bayer, signed on as president. "I was stunned. Never had I seen data like this," says Unterbeck, now Memory's chief science officer.

Now Kandel is devising a Rolipram-like drug that targets the brain's memory centers but avoids regions that control the vomiting reflex. It turns out some 20 variants of phosphodiesterase-4 play different roles. Memory Pharmaceuticals researchers carefully mapped the regions in the brain where each variant is found. It is testing prototype drugs that block those present only in the hippocampus. In animal tests, the compounds duplicate Rolipram's success without the nasty side effects. The first human trials are about 18 months away, most likely first in Alzheimer's. Says Unterbeck, "If it is safe, the market is incalculable."

Tully's Helicon Therapeutics is keeping pace. Under the direction of veteran biotech executive John Tallman, Helicon has screened 200,000 compounds for ones that boost CREB and cyclic-AMP, producing several drug candidates. So far Helicon's compounds have enabled mice to learn events associated with mild electric shocks twice as fast as normal. A legal showdown between Helicon and Memory may be in the cards. Helicon chief John Tallman says its CREB patent may prevent other companies from marketing memory drugs that target CREB pathways.Numerous other brain molecules are involved in memory, and some may offer even better drug targets than CREB and cyclic-AMP. Cortex Pharmaceuticals in Irvine, Calif. has designed molecules, called ampakines, that amplify incoming signals from other neurons by targeting so-called AMPA receptors on brain cells. With a partner, it is beginning a second-stage trial with 160 patients with mild cognitive impairment. Another firm, Axonyx in New York City, hopes to begin human trials next year of a drug derived from the saliva of the gila monster.Tully and Kandel also are looking for additional genes and proteins beyond CREB. Both are using DNA chips to scan thousands of genes at once. Success, says Tim Tully, is only a matter of time: "It's not an 'if'--it's a 'when.'"

Tonight I took enough of this stack that I started getting rather annoying spontaneous wood. This is due to PDE 5 Inhibition that comes rather annoyingly with the lovely PDE4 Inhibition. PDE5 inhibition also happens to be the mechanism of action of cialis, viagra and epimedium (horny goat weed). This is certainly a limiting factor for me for how much PDE I am going to inhibit as I don't want to go to the hospital, like those Cialis ads advise, if you have an erection for more than 4 hours.

When my PDE is this inhibited I also get this bizarre craving to watch Khan lecture about advanced math. Normally I can't stand it. In my humble opinion there is something interesting here. This could all be delusional hypomania though .

Sort of cross posting here, since this may be a better thread to discuss the topic.

I'm curious to know if there's been any members that have seen positive results with a stack to inhibit PDE4 and Prolyl Endopeptidase, such as Luteolin, Reservatrol, Forskolin, and Rosemary (or Berberine and Baicalin), and what sort of dosages were used.

I would go on an Isochroma like rant about this stack.... but maybe it's all just placebo you know. Nevertheless I've taken it for 2 months with what I think are good results without having any seriously bad things happen.

I would go on an Isochroma like rant about this stack.... but maybe it's all just placebo you know. Nevertheless I've taken it for 2 months with what I think are good results without having any seriously bad things happen.

This whole forum is about things that are experimental, possibly placebo, and about things that we might find out in 10 years are slowly killing us... at least that's the impression I am under when I read posts here.

Monoamine transporters playing major roles in regulating normal and abnormal synaptic activity are associated with various neuropsychological disorders. In spite of the discovery of a series of structurally different monoamine transporter antagonists for the therapy approach, no practical pharmaceutical can act as a transporter activator. Here, we isolated luteolin and apigenin from the fruit of Perilla frutescens (L.) Britt by using an activity-guided extraction technique, and proved that the two compounds possess actions of enhancing monoamine uptake either upon monoamine-transporter transgenic Chinese hamster ovary (CHO) cells or upon wild dopaminergic cell lines, with higher specificity for dopamine (DA) uptake than for norepinephrine (NE)- and serotonin (5HT)-uptake, as well as with more potency and greater efficacy for luteolin than for apigenin. Further, in the transgenic cells, the principal NE/DA uptake activation by luteolin was significantly prevented by respective transporter inhibitor, and the transmitter-uptake-enhancing action was independent of its ligands, which is in support of the compounds as monoamine transporter activators. Furthermore, luteolin evoked a marked disinhibition of cocaine-targeted effect in CHO cells overexpressing dopamine transporter. Thus, luteolin and apigenin function as monoamine transporter activators, which would improve several hypermonoaminergic neuropsychological disorders, especially cocaine dependence, through up-regulating monoamine transporter activity.

If I'm reading this right, then luteolin would increase reuptake of Dopamine. Wouldn't this make it harder to concentrate, making learning more difficult?

Also, I'm sure that this is Brain Science 101, but what would luteolin do in the presence of a non-reversible MAOI-B, like Selegiline?

If I'm reading this right, then luteolin would increase reuptake of Dopamine. Wouldn't this make it harder to concentrate, making learning more difficult?

Also, I'm sure that this is Brain Science 101, but what would luteolin do in the presence of a non-reversible MAOI-B, like Selegiline?

Luteolin probably does a lot of things. The Mechanism of action that I am talking about in this thread involves lowering PDE4 and increasing cAMP thus leading to intracellular cAMP build up leading to easier activation of the CREB protein which is the protein that takes short term memory and converts it into long term memory. Dopamine metabolism, as discussed in your study, is only tangentially related to all this.

Luteolin probably does a lot of things. The Mechanism of action that I am talking about in this thread involves lowering PDE4 and increasing cAMP thus leading to intracellular cAMP build up leading to easier activation of the CREB protein which is the protein that takes short term memory and converts it into long term memory. Dopamine metabolism, as discussed in your study, is only tangentially related to all this.

True. I was traversing information about Luteolin across several threads and lost sight of what this thread was originally about.

Consequently, I did wander down to the health store and purchase Artichoke extract, Rosemary, Forskolin, and Resveratrol. I had Oregon Grape, Goldenseal, and Celery Seed extract in my basket, but I was already over budget.

I have been on the Artichoke/Forskolin combo for a couple weeks now. I'm getting ready to start a trial run with Memantine, and I will probably cut out most of my supplements at first so that there are no interactions. After I get a baseline established, I will probably try to add some back in, if they are synergistic.

Would anyone care to hypothesize on how the possible cLTP increasing effects discussed in this thread (inhibiting PDE4 + increasing cAMP) would be affected by Memantine, given that it works on regulating the NMDA receptors?

The study cited in your original post seems relevant, however, I am not sure what the final outcome would be. At first glance, I took it to mean that the possible cLTP effects would be nullified by Memantine.

I have been on the Artichoke/Forskolin combo for a couple weeks now. I'm getting ready to start a trial run with Memantine, and I will probably cut out most of my supplements at first so that there are no interactions. After I get a baseline established, I will probably try to add some back in, if they are synergistic.

How's that stack working for you? I usually take 2 to 3 artichoke and a Forskolin and 500mg Resveratrol. Do you feel anything? I get better scores on cambridgebrainsciences.com challenge after I take it. The effect seems to last for several hours.

PDE4 is related to Dopamine which operates independently of NMDA receptors, AFAIK.

3. Take 2 (you can go up to 3 later) NOW Artichoke Extract Tablets and 1 Solaray Forskolin pill.

4. Wait 1 hour.

5. Play challenge again. I do consistently better on Spatial Search with this stack and do pretty well on everything else. This effect lasts for about 2 - 4 hours.

Anyway. Give it a shot. It's a super cheap all-natural stack and quite effective. I have scored up to 14 (97 percentile) using this stack on Spatial Search. You can also try this with Luteolin and Resveratrol which have some scientific research indicating they are PDE4 inhibitors but they are expensive and of much shorter duration.

Since this thread is concerning Chemically Induced LTP, this post may be misplaced, but I do plan to revisit this thread with quantitative details concerning memory.

I have to credit abelard lindsay with the past three weeks of successfully eliminating my ADD/SCT/Low Energy/Low Motivation. Seriously, I don't know why this is such a potent combination, but the artichoke/forskolin combo has had ridiculous benefits for me.

I took them by themselves for a couple weeks. By itself, the combo has an very interesting effect that is hard for me to describe. I don't know if it has to do with increased blood flow to the brain or what, but about 30 minutes after taking the artichoke/forskolin combo, my head feels... different. Less cramped. More open. Kind of like someone opened the windows to my stuffy attic and let the breeze blow in.

I didn't benchmark my results with any quantitative tests, but I did feel "sharper," and noticed increased mental and physical stamina.

However, I was still having major issues with motivation and drive. The only thing that I've ever found to help this has been Adderall. Now, I'm not a fan of Adderall, because of the side effects and long term brain destruction issues. If you want to know more about why I decided to go back on it, you can read through this thread. But I will tell you this: About 2 years ago, I would take 20mg of Adderall IR and it would wear off in about 4 hours with terrible side effects. Not to mention that the side effects would get in the way of me actually doing what I needed to do.

However, I am now taking 5mg of Adderall IR, 5mg of Selegiline, in combination with artichoke/forskolin. The positive effects last nearly all day, with drastically reduced side effects, and a much greater sense of overall well-being. The bp/heart rate is a bit high from the Adderall, but drastically reduced from where it was when I was taking 20mg Adderall, 3 times a day; I take Jiaogulan to reduce it. I still get muscle cramping after a 3-4 hours, but I take Magnesium L-Threonate and it successfully prevents it. I'm still working out some small kinks in the timing and dosage of when to take what. On days that I don't get it right, I get mildly shaky hands for about an hour in the morning, and I notice a bit of a mood decline in the evening. But I should stress that in comparison to the giant list of side effects that I used to have from Adderall alone, the few I have now are not even in the same magnitude, and very tolerable.

I have taken this combination for 3 weeks with great success, and so far, no issues with tolerance. I feel like the Magnesium may have helped prevent this, as well. Days that I have deviated from the regimen (such as skipping the Adderall or Artichoke), I notice a pretty large hit in my ability to get done what I need to do.

I also have some other information to jot about this stack, along with some discussion of other positive synergistic combinations.

I'm nearly afraid that I'm going to find out that this combination is somehow slowly killing me or eating holes in my brain. It works so well where nothing else has. I've gotten so much work done these past few weeks that I have been unable to do for months and months, and I've felt good while doing it! I think clearly, and have a much easier time prioritizing, and then following through with my plans. Not to mention that the tangible benefits I have enjoyed reach beyond the cognitive realm (increased muscle and libido, anyone?).

When I first started taking this stack, I went through the entire Khan Academy match exercise set. That's like 260 exercises... and it was fun. There is no way I would have done that without this. Math usually drives me nuts. This is some seriously good stuff and it's super cheap and all natural. I really can't express how blown away I've been by this stack. One other odd thing is it would make me get perfect scores on Lumosity memory match and over 7000 on Brain Shift which according to Lumosity is 1700 bpi or basically the highest you can score.

I agree that Threonate is pretty good stuff too. It makes me sleep well and then I get a stream of memories readily popping into my head throughout the day that would have been difficult to summon otherwise..